Loss of dopamine neurons leads to many of the clinical features of Parkinson disease (PD) but does not account for the progression of critical axial motor features, including postural instabiliy and gait impairments that tend to be refractory to dopaminergic medications and play a large role in disability. We recently published cross-sectional findings linking cardiovascular risk factors with the rate of axial motor feature accrual in PD. This effect was partially explained by the severity of chronic microvascular pathology, measured as white matter hyperintensities (WMHs) seen on brain MRI. If microvascular brain pathologies are responsible for causing medication-refractory motor impairments in PD, the early identification and treatment of high-risk subjects using targeted cardiovascular risk factor reduction interventions has the potential to serve as a disease modifying strategy impacting the health care of many Veterans with PD, in whom cardiovascular comorbidities are seen more commonly. In order to design effective clinical trials aimed at lowering complications due to comorbid microvascular brain pathology, however, a more detailed understanding of the mechanistic link between cardiovascular risk factors and clinically meaningful outcomes is essential. I propose to study the impact of cardiovascular risk factors and microvascular brain pathology on axial motor features in a 2-year longitudinal cohort study of individuals with early Parkinson disease. Aim 1 will test a longitudinal hypothesis drawn from our preliminary cross-sectional data: PD patients with greater baseline cardiovascular risk factor burden develop more rapid progression of axial motor features and greater WMH burden at 2 year follow-up. Aim 2 will use arterial spin labeling (ASL) MRI to identify regional impairments in cerebral blood flow (CBF) and cerebrovascular reserve capacity (CvRC) in early PD subjects with cardiovascular risk factors before the progression to irreversible microvascular injury takes place. These studies will not only serve as a novel natural history study of microvascular changes in PD, they will also facilitate the identification of PD subjects at highest risk for comorbid microvascular changes, permitting the design of a future intervention trial focused on targeted, early cardiovascular risk factor reduction. The goal of thi potential disease modifying strategy would be to slow the rate of medically refractory axial motor feature accrual in Veterans with PD. If successful, this approach would have implications for other neurodegenerative conditions as well. The practical experience of this project along with the formal training plan in neuroimaging, epidemiology, and clinical trials methodology included in this CDA-2 proposal will facilitate my career growth into a MERIT-funded clinician-investigator who aims to usher novel therapeutic strategies into the realm of PD clinical trials.